PROJECT SUMMARY: This is a 5 year competitive renewal that builds upon nearly a decade of previously funded research that has identified the projection from the prefrontal cortex to the nucleus accumbens, and then to the ventral pallidum as a key brain circuit underlying relapse to cocaine use. Relapse is modeled in rats trained to self-administer cocaine and then undergone extinction training, and is defined as the reinstatement of cocaine seeking in response to a conditioned cue, a noncontingent injection of cocaine, or after inhibition of the infralimbic cortex that is hypothesized to disinhibit extinguished responding. In the first aim of the present proposal we will use the recent development of genetically targeted light- activated proteins to validate the role of this circuitry in the reinstatement of cocaine seeking. Previous pharmacological or electrical stimulation techniques used to define brain circuitry suffer caveats such affecting fibers of passage and/or multiple projections from a given nucleus, and these weaknesses are largely circumvented using in vivo light activation of virally transfected channels or transporters. Thus, the first aim is devoted to refining this new technology and validating, or not, previous circuitry studies by our group and others identifying the PFC-accumbens-pallidal circuit as important in relapse. The remaining 3 aims focus on our recent finding that dendritic spine morphology in the nucleus accumbens undergoes rapid and profound changes during a cocaine-primed reinstatement of drug seeking. Firstly, in Aim 2 we will fully characterize these morphological changes in both the core and shell subcompartments of the accumbens in response to different modalities of inducing cocaine seeking (e.g. cue, cocaine and inhibition of infralimbic cortex). Then in Aim 3 we will determine which afferents to the nucleus accumbens are mediating the reinstatement-associated morphological changes, with a focus on glutamatergic inputs from the prefrontal cortex and amygdala, and dopaminergic inputs from the ventral tegmental area. Finally in Aim 4 we conduct experiments to determine if the changes in spine morphology are necessary for reinstating cocaine seeking, or if they are protective and inhibit reinstatement. Accordingly, we will test the capacity of 3 different inhibitors of actin dynamics to simultaneously inhibit primed reinstatement and reinstatement-associated spine morphology. Interestingly, preliminary data presented in the proposal indicates that the rapid morphological changes may be protective rather than causal in reinstating cocaine seeking.